Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with 'normal' developmental myelination.

Global Use of Idarucizumab in Clinical Practice: Outcomes of the RE-VECTO Surveillance Program.

Idarucizumab was approved for the reversal of dabigatran in 2015. We investigated whether postapproval usage patterns of idarucizumab in a real-world setting reflect those observed in the pivotal trials. No safety or efficacy data were collected in this medical record-based observational study. RE-VECTO, a global postapproval, international, surveillance program, involved hospital pharmacies in countries where idarucizumab was licensed and dispensed (August 2016-June 2018). Characteristics of sites prescribing idarucizumab and of eligible patients (≥ 18 years old and receiving idarucizumab regardless of prior oral anticoagulant use), as well as idarucizumab utilization data, were collected and analyzed descriptively. Sixty-one sites enrolled 359 patients. Most pharmacies (85.2%) were centralized, and the median idarucizumab units stocked per hospital was 2.0 (interquartile range, 1.0-3.0). Almost three-quarters of patients were elderly (74.9% aged > 70 years), and only four (1.1%) had received idarucizumab before. Nearly all patients were treated with dabigatran (97.5%). There was a low frequency of unapproved dabigatran dosage regimens (3.3%). Life-threatening or uncontrolled bleeding was the most frequent indication for idarucizumab (57.7%), followed by emergency surgery/urgent procedure (35.9%). Of the life-threatening bleeding events, the most frequent were gastrointestinal tract (44.4%) and intracranial (38.6%). Most patients (95.0%) were given the full dose of two vials (2 × 2.5 g) of idarucizumab initially, and very few (1.7%) received a second dose. Of those patients requiring emergency or scheduled/planned surgery/procedures, 25.5% underwent gastrointestinal and/or abdominal surgery/procedures. Real-world usage patterns of idarucizumab provide valuable insights into emergency reversal strategies. Off-label use was minimal.

Healthcare resource utilization in patients receiving idarucizumab for reversal of dabigatran anticoagulation due to major bleeding, urgent surgery, or procedural interventions: interim results from the RE-VERSE AD™ study.

AIMS: Patients treated with anticoagulants may experience serious bleeding or require urgent surgery or intervention, and may benefit from rapid anticoagulant reversal. This exploratory analysis assessed healthcare resource utilization (HCRU) in patients treated with idarucizumab, a specific reversal agent for dabigatran etexilate. MATERIALS AND METHODS: RE-VERSE AD™ (NCT02104947), a prospective, multi-center open-label study, is evaluating idarucizumab for dabigatran reversal in patients with serious bleeding (Group A) or undergoing emergency surgery/procedures (Group B). HCRU outcome measures evaluated in the first 90 patients enrolled were use of blood products and pro-hemostatic agents, length of stay (LOS) in hospital, and LOS in intensive care unit (ICU). RESULTS: Blood products or pro-hemostatic agents were given to 63% (32/51) of patients in Group A and 23% (9/39) of patients in Group B on the day of/day after surgery. An overnight hospital stay was reported for 82% (42/51) of patients in Group A with median LOS = 7 (range = 1-71) bed-days. For Group B, 92% (36/39) had an overnight hospital stay with a median LOS = 9 (range = 1-92) bed-days. In Group A, 17 patients were admitted to the ICU for at least 1 day with median LOS = 4 (range = 1-44) days; in Group B the number was 15 with median LOS = 2 (range = 1-92) days. LIMITATIONS: The lack of a control group and the small patient numbers limit the strength of the conclusions. CONCLUSIONS: The use of idarucizumab may simplify emergency management of dabigatran-treated patients with life-threatening bleeds and reduce perioperative complications in patients undergoing emergency surgery.

Enhanced elimination of dabigatran: Identifying the appropriate patient for the use of continuous venovenous hemodialysis instead of intermittent hemodialysis-A simulation analysis.

There are clinical situations where rapid elimination of dabigatran is beneficial. Intermittent hemodialysis (IHD) removes dabigatran effectively but is not always available and requires a hemodynamically stable patient. We therefore investigated the continuous venovenous hemodialysis (CVVHD) technique for its potency in the elimination of dabigatran. Based on pharmacometric characterization of dabigatran in IHD, we simulated a broad range of dialysis settings for CVVHD and then applied the model to specific clinical situations. Dialysis of 3 hours' duration with typical clinical settings (dialysate flow rate 50 mL/min; blood flow rate 150 mL/min) reduced dabigatran plasma concentration by 14-17% in addition to the patient body clearance. Extending dialysis duration to 8 or 16 hours for patients with severe renal dysfunction resulted in additional reductions from 26% up to 40%. When comparing with IHD for different endpoints (reaching 50% of initial dabigatran concentration, or nondetectability of dabigatran by the Hemoclot test), CVVHD did not reach comparable elimination rates. CVVHD is not fast enough to prepare for urgent interventions in patients with high bleeding risks. However, in situations where less hemodynamically stressful modalities seem indicated, CVVHD might be useful in moderately to severely renally impaired patients to accelerate dabigatran elimination.

Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.

Axon-glial interaction in the CNS: what we have learned from mouse models of Pelizaeus-Merzbacher disease.

In the central nervous system (CNS) the majority of axons are surrounded by a myelin sheath, which is produced by oligodendrocytes. Myelin is a lipid-rich insulating material that facilitates the rapid conduction of electrical impulses along the myelinated nerve fibre. Proteolipid protein and its isoform DM20 constitute the most abundant protein component of CNS myelin. Mutations in the PLP1 gene encoding these myelin proteins cause Pelizaeus-Merzbacher disease and the related allelic disorder, spastic paraplegia type 2. Animal models of these diseases, particularly models lacking or overexpressing Plp1, have shed light on the interplay between axons and oligodendrocytes, and how one component influences the other.

Intraaxial spinal cord hemorrhage secondary to atlantoaxial subluxation in a dog.

A 1-year-old, 3.5-kg, spayed female, toy poodle was presented for acute-onset tetraplegia and neck pain. Neuroanatomical diagnosis was consistent with a first through fifth cervical (C(1) through C(5)) spinal cord lesion. Radiographs of the cervical vertebral column revealed atlantoaxial (AA) subluxation. Magnetic resonance imaging revealed abnormalities consistent with intraaxial spinal cord hemorrhage at the level of the AA articulation. The dog was treated with external coaptation. After 8 days, the dog regained voluntary motor function in all four limbs. Surgical stabilization was pursued. Postoperatively, the dog regained the ability to ambulate. This report details the imaging findings and management of a dog with intraaxial spinal cord hemorrhage secondary to AA subluxation.

Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease.

It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and 'damaged' myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term.

Evaluation of the anatomic effect of physical therapy exercises for mobilization of lumbar spinal nerves and the dura mater in dogs.

OBJECTIVE: To adapt and standardize neural tissue mobilization exercises, quantify nerve root movement, and assess the anatomic effects of lumbar spinal nerve and dural mobilization in dogs. ANIMALS: 15 canine cadavers. PROCEDURES: 5 cadavers were used in the preliminary part of the study to adapt 3 neural tissue mobilization physical therapy exercises to canine anatomy. In the other 10 cadavers, the L4 to L7 nerve roots and the dura at the level of T13 and L1 were isolated and marked. Movements during the physical therapy exercises were standardized by means of goniometric control. Movement of the nerve roots in response to each exercise was digitally measured. The effects of body weight and crownrump length on the distance of nerve root movement achieved during each exercise were also assessed. Each exercise was divided into 4 steps, and the overall distance of neural movement achieved was compared with distances achieved between steps. RESULTS: Neural tissue mobilization exercises elicited visible and measurable movement of nerve roots L4 to L7 and of the dura at T13 and L1 in all cadavers. CONCLUSIONS AND CLINICAL RELEVANCE: The physical therapy exercises evaluated had measurable effects on nerve roots L4 to L7 and the dura mater in the T13 and L1 segments. These exercises should be evaluated in clinical trials to validate their efficacy as primary treatments or ancillary postsurgical therapy in dogs with disorders of the thoracolumbar and lumbosacral segments of the vertebral column.